The N-methyl D-aspartic acid receptor (NMDAR) complex includes more than 60 proteins [4]. The NMDAR complex has been reported to be associated with several neurological diseases and disorders, including stroke, neurotrauma, neurodegenerative diseases, memory and long term potentiation, optical and aural neuropathies, pain, and more. However, several attempts to inhibit the NMDAR complex directly have failed in the clinic because of excessive side effects.
Post-synaptic Density protein 95 kD (PSD95) binds directly to the C-terminal NR2 subunits of the NMDAR [11] via its first two PDZ domains, PDZ1 and PDZ2 [12]. It has been reported that that disrupting the interaction between PSD95 and NMDAR can protect animals from the damaging effects of stroke without blocking the electrical and calcium flux activities of the NMDAR[13].
NADH dehydrogenase subunit 2 (ND2) has been reported to associate with the tyrosine kinase Src (see FIG. 1A). Src is one of several Src family kinases (SFKs) in the NMDAR complex (i.e. Src, Fyn, Lyn and Yes) [5-7]. Src is involved in the control of many functions, including cell adhesion, growth, movement and differentiation. Src is widely expressed in many cell types, and can have different locations within a cell. It appears that the subcellular location of Src can affect its function. Src can associate with cellular membranes, such as the plasma membrane, the perinuclear membrane and the endosomal membrane. At the plasma membrane, Src can transduce signals from a variety of receptors to internal signalling pathways that convey these signals to the nucleus, cytoskeleton and other cellular components. For example, Src can act through the growth factor receptors to affect cell growth and proliferation.
A presumed molecular arrangement between NMDARs, Src and ND2 has been presented in of Liu et al., Nat Med 2008, in which Src is assumed to interact with NMDARs via ND2 which acts as an adapter protein. ND2 anchors Src to the N-methyl-d-aspartate (NMDA) receptor complex in postsynaptic densities (PSDs) to regulate NMDA receptor activity. It has been reported a fragment of Src termed Src 40-49-Tat can inhibit interactions between Src and ND2 at excitatory synapses in the brain, reducing phosphorylation of NR2B subunits and modulating pain [1, 2, 3].